Gastroenterologie
a hepatologie

Gastrointestinal disorders in patients with common variable immunodeficiency

Pavlína Králíčková¹, Štěpán Šembera ^{Orcid.org  2}, Kateřina Kamarádová^3,4, Ilja Tachecí²

+ Affiliation
¹ Ústav klinické imunologie a alergologie, LF UK a FN Hradec Králové
² II. interní gastroenterologická klinika LF UK a FN Hradec Králové
³ Fingerlandův ústav patologie, LF UK a FN Hradec Králové
⁴ Unilabs Pathology, k.s., Laboratoř Praha

Summary

Common variable immunodeficiency (CVID) is a group of inherited antibody immune disorders. Patients often suffer from recurrent bacterial infections, autoimmune or dysregulatory complications, and have an increased risk of developing cancer (e. g., lymphoma, gastric cancer). The most common gastrointestinal pathogens include Helicobacter pylori, Campylobacter jejuni, and Giardia lamblia; in more severe cases, norovirus or cytomegalovirus (CMV) may cause significant diarrhoea. Bacterial overgrowth syndrome is also common. CVID is associated with alterations in the microbio­me, which contributes to complications in distant organs such as the lungs and liver. Non-infectious complications can affect the entire gastrointestinal tract. Notable examples include intestinal metaplasia of the gastric mucosa with a risk of carcinoma, enteropathy mimicking celiac dis­ease, inflammatory bowel dis­ease-like colitis, nodular regenerative hyperplasia, and pre-portal hypertension. These complications typically develop slowly and subtly over time. Once malnutrition sets in, irreversible changes to the intestinal mucosa are often present. Managing CVID requires a multidisciplinary approach and regular screening. Endoscopic examinations, including repeated and multiple bio­psies, are essential for accurate dia­gnosis. Elastography is suitable for detecting hepatopathies. Serological blood tests are generally not helpful. Treatment is challenging and should be individualized. Immunoglobulin replacement therapy reduces the frequency of infections only. In cases of non-infectious complications, immunomodulatory therapy is required and, tailored to the patient’s genetic background, if possible.

Keywords

imunodeficience běžná variabilní, endoscopic treatment, intestinal dis­eases, malabsorption syndrome, liver dis­ease, microbiota, imunomodulace

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Literature

1. Chovancová Z, Hlaváčková E, Milota T et al. Substituční imunoglobulinová léčba v České republice: data z Národního registru primárních imunodeficiencí ke konci roku 2020. Alergie 2022; 24(1): 13– 21.
2. Cunningham-Rundles C, Casanova JL, Boisson B. Genetics and clinical phenotypes in common variable immunodeficiency. Front Genet 2024; 14: 1272912. doi: 10.3389/ fgene.2023.1272912.
3. Seidel MG, Kindle G, Gathmann B et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical dia­gnosis of inborn errors of immunity. J Allergy Clin Immunol Pract 2019; 7(6): 1763– 1770. doi: 10.1016/ j. jaip.2019.02.004.
4. Carrabba M, Salvi M, Baselli LA et al. Long-term fol­low-up in common variable immunodeficiency: the pediatric-onset and adult-onset landscape. Front Pediatr 2023; 11: 1125994. doi: 10.3389/ fped.2023.1125994.
5. Thalhammer J, Kindle G, Nieters A et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol 2021; 148(5): 1332.e5– 1341.e5. doi: 10.1016/ j. jaci.2021.04.015.
6. Yazdani R, Habibi S, Sharifi L et al. Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, dia­gnosis, classification, and management. J Investig Allergol Clin Immunol 2020; 30(1): 14– 34. doi: 10.18176/ jiaci.0388.
7. Kralickova P, Milota T, Litzman J et al. CVID-associated tumors: Czech Nationwide Study focused on epidemiology, immunology, and genetic background in a cohort of patients with CVID. Front Immunol 2019; 9: 3135. doi: 10.3389/ fimmu.2018.03135.
8. Bez P, Smits B, Geier C et al. Uncovering risk factors of premature mortality in Common Variable Immunodeficiency (CVID). J Allergy Clin Immunol Pract 2025; 13(5): 1201.e10– 1209.e10. doi: 10.1016/ j. jaip.2025.03.009.
9. Franzblau LE, Fuleihan RL, Cunningham-Rundles C et al. CVID-associated intestinal disorders in the USIDNET registry: an analysis of dis­ease manifestations, functional status, comorbidities, and treatment. J Clin Immunol 2023; 44(1): 32. doi: 10.1007/ s10875-023-01604-6.
10. Sanchez DA, Rotella K, Toribio­ C et al. Characterization of infectious and non-infectious gastrointestinal dis­ease in common variable immunodeficiency: analysis of 114 patient cohort. Front Immunol 2023; 14: 1209570. doi: 10.3389/ fimmu.2023.12095708.
11. Woodward J, Gkrania-Klotsas E, Kumara- ratne D. Chronic norovirus infection and common variable immunodeficiency. Clin Exp Immunol 2017; 188(3): 363– 370. doi: 10.1111/ cei.12884.
12. Kralickova P, Mala E, Vokurkova D et al. Cytomegalovirus dis­ease in patients with common variable immunodeficiency: three case reports. Int Arch Allergy Immunol 2014; 163(1): 69– 74. doi: 10.1159/ 000355957.
13. Motta-Raymundo A, Rosmaninho P, Santos DF et al. Contribution of helicobacter pylori to the inflammatory complications of common variable immunodeficiency. Front Immunol 2022; 13: 834137. doi: 10.3389/ fimmu.2022.834137.
14. Baniadam L, Arshi S, Nabavi M et al. Can concurrent lower gastrointestinal manifestations help the timely dia­gnosis of small intestinal bacterial overgrowth in CVID patients? Eur Ann Allergy Clin Immunol 2021; 53(1): 18– 22. doi: 10.23822/ EurAnnACI.1764-1489.137.
15. Varricchi G, Poto R, Ianiro G et al. Gut microbio­me and common variable immunodeficiency: few certainties and many outstanding questions. Front Immunol 2021; 12: 712915. doi: 10.3389/ fimmu.2021.712915.
16. Jørgensen SF, Trøseid M, Kummen M et al. Altered gut microbio­ta profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. Mucosal Immunol 2016; 9(6): 1455– 1465. doi: 10.1038/ mi.2016.18.
17. Yang M, Kaarbø M, Myhre V et al. Altered genome-wide DNA methylation in the duodenum of common variable immunodeficiency patients. J Clin Immunol 2024; 44(6): 133. doi: 10.1007/ s10875-024-01726-5.
18. Macpherson ME, Skarpengland T, Hov JR et al. Increased plasma levels of triglyceride-enriched lipoproteins associate with systemic inflammation, lipopolysaccharides, and gut dysbio­sis in common variable immunodeficiency. J Clin Immunol 2023; 43(6): 1229– 1240. doi: 10.1007/ s10875-023-01475-x.
19. Jørgensen SF, Reims HM, Frydenlund D et al. A cross-sectional study of the prevalence of gastrointestinal symptoms and pathology in patients with common variable immunodeficiency. Am J Gastroenterol 2016; 111(10): 1467– 1475. doi: 10.1038/ ajg.2016.329.
20. Wroblova K, Kolorz M, Pav I et al. Frequencies of HLA-DQ2 and HLA-DQ8 haplotypes in Czech and Slovak coeliac patients and the healthy population. Acta Biochim Pol 2014; 61(1): 191– 193.
21. Andersen IM, Jørgensen SF. Gut inflammation in CVID: causes and consequences. Expert Rev Clin Immunol 2022; 18(1): 31– 45. doi: 10.1080/ 1744666X.2021.2008241.
22. Velthof L, Geldof J, Truyens M et al. Gastrointestinal dis­ease in Common Variable Immunodeficiency Disorder (CVID): histological patterns, dia­gnostic clues and pitfalls for the pathologist and gastroenterologist. J Clin Med 2025; 14(2): 497. doi: 10.3390/ jcm14020497.
23. Daza-Cajigal V, Segura-Guerrero M, López-Cueto M et al. Clinical manifestations and approach to the management of patients with common variable immunodeficiency and liver dis­ease. Front Immunol 2023; 14: 1197361. doi: 10.3389/ fimmu.2023.1197361.
24. Baumert LS, Shih A, Chung RT. Management of liver dis­ease and portal hypertension in Common Variable Immunodeficiency (CVID). JHEP Rep 2023; 5(11): 100882. doi: 10.1016/ j. jhepr.2023.100882.
25. DiGiacomo DV, Shay JE, Crotty R et al. Liver stiffness by transient elastography correlates with degree of portal hypertension in common variable immunodeficiency patients with nodular regenerative hyperplasia. Front Immunol 2022; 13: 864550. doi: 10.3389/ fimmu.2022.864550.
26. Globig AM, Strohmeier V, Surabattula R et al. Evaluation of laboratory and sonographic parameters for detection of portal hypertension in patients with common variable immunodeficiency. J Clin Immunol 2022; 42(8): 1626– 1637. doi: 10.1007/ s10875-022-01319-0.
27. De Gottardi A, Rautou PE, Schouten J et al. Porto-sinusoidal vascular dis­ease: proposal and description of a novel entity. Lancet Gastroenterol Hepatol 2019; 4(5): 399– 411. doi: 10.1016/ S2468-1253(19)30047-0.
28. Výbor České společnosti alergologie a klinické imunologie. Návrh standardu imunoglobulinové léčby nemocných s protilátkovými imunodeficiencemi. 2016 [online]. Dostupné z: https:/ / www.csaki.cz/ soubory/ stanoviska-a-doporuceni/ 13.-Navrh-standardu-imunoglobulinove-lecby.pdf.
29. Jørgensen SF, Macpherson ME, Bjørnetrø T et al. Rifaximin alters gut microbio­ta profile, but does not affect systemic inflammation –  a randomized controlled trial in common variable immunodeficiency. Sci Rep 2019; 9(1): 167. doi: 10.1038/ s41598-018-35367-7.
30. Napiórkowska-Baran K, Biliński J, Pujanek M et al. Fecal microbio­ta transplantation in a patient with chronic diarrhea and primary and secondary immunodeficiency (common variable immunodeficiency and splenectomy). Front Cell Infect Microbio­l 2024; 14: 1456672. doi: 10.3389/ fcimb.2024.1456672.
31. Sousa eSilva R, Pereira da Silva S, Luís R et al. Nodular regenerative hyperplasia in CVID patients: could low-dose oral glucocorticoids be part of the solution? Eur Ann Allergy Clin Immunol 2023; 55(6): 313– 315. doi: 10.23822/ EurAnnACI.1764-1489.251.
32. Fevang B. Treatment of inflammatory complications in Common Variable Immunodeficiency (CVID): current concepts and future perspectives. Expert Rev Clin Immunol 2023; 19(6): 627– 638. doi: 10.1080/ 1744666X.2023.2198208.
33. Marley F, Lockett M, Gompels M et al. A patient with CVID-enteropathy successfully treated with ustekinumab. Immunol Res 2024; 73(1): 19. doi: 10.1007/ s12026-024-09559-5.
34. Azzu V, Elias JE, Duckworth A et al. Liver transplantation in adults with liver dis­ease due to common variable immunodeficiency leads to early recurrent dis­ease and poor outcome. Liver Transpl 2018; 24(2): 171– 181. doi: 10.1002/ lt.24979.
35. Hashem H, Ghatasheh L, Najjar R et al. Outcomes of hematopoietic cell transplantation in children with inborn errors of immunity: a single-center series. J Clin Immunol 2024; 45(1): 59. doi: 10.1007/ s10875-024-01853-z.
36. Wehr C, Gennery AR, Lindemans C et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol 2015; 135(4): 988.e6– 997.e6. doi: 10.1016/ j. jaci.2014.11.029.
37. Albert MH, Sirait T, Eikema DJ et al. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study. Blood 2023; 141(18): 2284. doi: 10.1182/ blood.2023020298.
38. Fox TA, Massey V, Lever C et al. Pre-transplant immune dysregulation predicts for poor outcome fol­lowing allogeneic haematopoietic stem cell transplantation in adolescents and adults with Inborn Errors of Immunity (IEI). J Clin Immunol 2025; 45(1): 64. doi: 10.1007/ s10875-024-01854-y.
39. Tsilifis C, Speckmann C, Lum SH et al. Hematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: a European Society for Blood and Marrow Transplantation Inborn Errors Working Party study. J Allergy Clin Immunol 2024; 154(6): 1534– 1544. doi: 10.1016/ j. jaci.2024.08.020.
40. Tessarin G, Baronio M, Lougaris V. Monogenic forms of common variable immunodeficiency and implications on target therapeutic approaches. Curr Opin Allergy Clin Immunol 2023; 23(6): 461– 466. doi: 10.1097/ ACI.0000000000000947. 
41. Fischer M, Olbrich P, Hadjadj J et al. JAK inhibitor treatment for inborn errors of JAK/ STAT signaling: An ESID/ EBMT-IEWP retrospective study. J Allergy Clin Immunol 2024; 153(1): 275.e18– 286.e18. doi: 10.1016/ j. jaci.2023.10.018.